Autistic Spectrum Disorders (ASD) are a group of developmental disorders including autistic disorder, Asperger disorder and pervasive developmental disorder not otherwise specified, according to the Diagnostic and Statistical Manual of the American Psychiatric Association, Fourth Edition. The disorders have in common social disconnection and repetitive or stereotyped behaviors. In autistic disorder there is delayed or impaired language (http://www.cdc.gov/ncbddd/autism/hcp-dsm.html). There are many specific genetic and environmental factors associated with ASD which lead to a similar behavioral outcome. An intermediate phenotype appears to be a reduction in nicotinic cholinergic receptors in certain parts of the brain.
Perry et al (Am J Psychiatry 2001, 158:1058) compared autopsy brain tissue among 26 normal, autistic, Down's and other mental retardation patients, aged about 24-36 years. In the frontal and parietal cortices, α4β2 nicotinic receptors, as assessed by epibatidine binding, were reduced by about ⅔ in the autistic and mental retardation patients as compared to normal. The same laboratory compared nicotinic receptors in the thalamus, in which they are concentrated, in 3 autistic and 3 normal autopsy brains from patients aged 19-37. In the paraventricular and reuniens nuclei, α7 and β2 reactive neurons were decreased in the autistic patients' brains, although a4 immunoreactive neurons were not. (Ray et al, Neurobiol Disease, 2005, 19, 366) Based on the lack of activation of the “fusiform face area” known to occur when ASD patients are presented with strangers' faces, and the known cholinergic regulation of this area, PET studies of acetylcholinesterase activity were conducted in 20 young adult normal and ASD subjects, matched for I.Q. (Suzuki et al, Arch Gen Psychiatry 2011, 68, 3, 306) The ASD subjects had lower [11C]MP4A k3 values than controls, and those k3 values correlated inversely with their social disabilities as assessed by the Autism Diagnostic Observation Schedule as well as the Autism Diagnostic Interview-Revised. The authors conclude that the fusiform face area has deficient cholinergic innervation in ASD subjects and that this relates to their level of social functioning. Case reports, open-label and poorly documented studies of galantamine, a cholinesterase inhibitor and positive allosteric modulator of nicotinic receptors, in ASD have reported some beneficial results. (Niederhofer et al, BMJ 2002, 325, 1421; Hertzberg, Int J Psychiatry in Medicine 2003/2004, 33, 4, 395; Nicholson et al, J Child Adolesc Psychopharmacol 2006, 16, 5, 621) A review of cholinergic abnormalities in ASD suggests that nicotinic agonists and positive allosteric modulators might be helpful, and then summarizes studies of donepezil, rivastigmine and galantamine in ASD. (Deutsch et al, Clin Neuropharm 2010, 33, 114).
There is a genetic copy number variation which can impair the formation of α7 nicotinic receptors. This occurs in 15q113.3, and is associated with autism, mental retardation, schizophrenia and epilepsy. (Yasui et al, Hum Molec Genetics 2011, 20, 22) Within this segment of chromatin is a region whose deletion causes the Prader-Willi Syndrome. When the protein whose deletion causes Rett Syndrome, MeCP2, binds to this region, it overlaps the Prader-Willi region and these map to sites flanking CHRNA7, which encodes the nicotinic α7 receptor. This finding led to the analysis of frontal cortices from Rett and autism patients for CHRNA7 expression, and a decrease averaging 40%, most obvious at young ages, was found in comparison to controls. (FIG. 1) The finding of the 15q13.3 deletion syndrome in a patient with uncontrollable rage outbursts led to a trial of galantamine. (Cubells et al, Am J Med Genet Part A 2011, 155, 805) A striking decrease in episodes of rage was reported, although environmental changes could also have been responsible.
Mutations in the Mecp2 gene are found in the great majority of cases of Rett syndrome. However, reduced Mecp2 effects have been reported more broadly in autism spectrum disorders. In the valproic acid model of autism, Mecp2 expression is decreased in neural progenitor cells of both sexes and in the prefrontal cortex of males, who comprise most cases of autism. (Kim K C et al, Mol Neurobiol 2014, Nov. 18 (epub ahead of print)) In the cerebellum of autistic patients, decreased Mecp2 binding has been reported and hypothesized to be the cause of the failure of downregulation of the Engrailed-2 gene, which is overexpressed. (James S J, et al, Transl Psychiatry 2014, 4:e460, Doi: 10.1038/tp.2014.87)
In human postmortem cortical tissue, significantly reduced Mecp2 expression was found in 79% of cases of autism (11/14), 100% of Rett (9/9), 100% of Angelman, 75% of Prader Willi (3/4), 60% of Down's syndromes (3/5), and in both of 2 cases of attention deficit hyperactivity disorder, as compared to normal age-matched controls. (Nagarajan R P, et al, Epigenetics 2006, 1(4):e1-11).
Galantamine has the structure:

Galantamine is approved for the treatment of patients with mild to moderate Alzheimer's disease. It is not recommended for use in mild cognitive impairment due to increased mortality in that population.
U.S. Pat. No. 4,663,318, describes the use of galantamine, a known cholinesterase inhibitor, in the treatment of Alzheimer's disease. PCT publication WO 8808708, describes the use of analogs of galantamine and lycoramine for a similar purpose. U.S. Pat. No. 6,670,356, escribes the effects of analogs of galantamine and lycoramine in modulation of nicotinic receptors and in treating and retarding the progression of Alzheimer's and Parkinson's diseases, neuroprotection against neurodegenerative disorders. At the time of these patents, Alzheimer's disease understood to be a condition that manifested itself by dementia and its underlying causes were only beginning to be understood. The treatments described in these earlier patents addressed factors involved in such dementia, namely reducing the activity of acetylcholinesterase so as to limit the reduction in availability of the neurotransmitter acetylcholine that arises from the action of acetylcholinesterase thereon and indirect stimulation of nicotinic receptors by allosteric modulation thereof to improve their functioning.
The galantamine positive allosteric modulatory site is present on all nicotinic receptors which have been examined. (Samochocki et al, JPET 2003, 305, 1024) This mechanism may also be useful in the control of inflammation, pain, appetite, and depression.